Therapeutic potential and limitations of new FAK inhibitors in the treatment of cancer

Schultze, Alexander; Fiedler, Walter

doi:10.1517/13543784.2010.489548

Cited by 93 publications

(79 citation statements)

References 85 publications

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“…Subsequently, TAE226, a TKI that targets FAK and IGF-1R, was demonstrated to enhance docetaxel cytotoxicity (33); however, at this point, development stalled due to the drug failing clinical trials. Other firstgeneration FAK TKIs had problems with compensatory upregulation of the FAK homolog, Pyk2, which affected clinical efficacy (34). Newer FAK TKIs targeting FAK and Pyk2, PF-00562271, and its second-generation PF-04554878, were well tolerated in phase I clinical trials (35,36), and the latter is currently in phase Ib and II clinical trials (37).…”

Section: Discussionmentioning

confidence: 99%

Phosphoproteomic Profiling Identifies Focal Adhesion Kinase as a Mediator of Docetaxel Resistance in Castrate-Resistant Prostate Cancer

Lee

Hochgräfe

Lin

et al. 2014

Molecular Cancer Therapeutics

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Docetaxel remains the standard-of-care for men diagnosed with metastatic castrate-resistant prostate cancer (CRPC). However, only approximately 50% of patients benefit from treatment and all develop docetaxelresistant disease. Here, we characterize global perturbations in tyrosine kinase signaling associated with docetaxel resistance and thereby develop a potential therapeutic strategy to reverse this phenotype. Using quantitative mass spectrometry-based phosphoproteomics, we identified that metastatic docetaxel-resistant prostate cancer cell lines (DU145-Rx and PC3-Rx) exhibit increased phosphorylation of focal adhesion kinase (FAK) on Y397 and Y576, in comparison with parental controls (DU145 and PC3, respectively). Bioinformatic analyses identified perturbations in pathways regulating focal adhesions and the actin cytoskeleton and in protein-protein interaction networks related to these pathways in docetaxel-resistant cells. Treatment with the FAK tyrosine kinase inhibitor (TKI) PF-00562271 reduced FAK phosphorylation in the resistant cells, but did not affect cell viability or Akt phosphorylation. Docetaxel administration reduced FAK and Akt phosphorylation, whereas cotreatment with PF-00562271 and docetaxel resulted in an additive attenuation of FAK and Akt phosphorylation and overcame the chemoresistant phenotype. The enhanced efficacy of cotreatment was due to increased autophagic cell death, rather than apoptosis. These data strongly support that enhanced FAK activation mediates chemoresistance in CRPC, and identify a potential clinical niche for FAK TKIs, where coadministration with docetaxel may be used in patients with CRPC to overcome chemoresistance. Mol Cancer Ther; 13(1); 190-201. Ó2013 AACR.

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Section: Discussionmentioning

confidence: 99%

Phosphoproteomic Profiling Identifies Focal Adhesion Kinase as a Mediator of Docetaxel Resistance in Castrate-Resistant Prostate Cancer

Lee

Hochgräfe

Lin

et al. 2014

Molecular Cancer Therapeutics

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“…FAK inhibition in cancer has shown promise in terms of effectiveness and toxicity in early phase trials [29]. Thus, we hypothesised that targeting migration by FAK inhibition would be beneficial in PAH as well.…”

Section: Introductionmentioning

confidence: 99%

Targeting cell motility in pulmonary arterial hypertension

et al. 2013

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Pulmonary artery smooth muscle cells (PASMC), in pulmonary arterial hypertension (PAH), contribute to obliterative vascular remodelling and are characterised by enhanced proliferation, suppressed apoptosis and, a much less studied, increased migration potential. One of the major proteins that regulate cell migration is focal adhesion kinase (FAK), but its role in PAH is not fully understood. We hypothesised that targeting cell migration by FAK inhibition may be a new therapeutic strategy in PAH.In vivo, inhalation of FAK-siRNA (n55) or oral delivery of PF-228 (FAK inhibitor PF-573 228; n55) inhibited rat monocrotaline induced PAH, improving the haemodynamics, vascular remodelling (media thickness), and right ventricular hypertrophy. In vitro, FAK was activated in PAH human lungs (n58) or PASMC when compared to those form healthy subjects (Western blot, n55), in a Src-dependent manner, as it was reversed by the specific Src inhibitor PP2. The degree of FAK phosphorylation at Y576 correlated positively with pulmonary vascular resistance in PAH patients. FAK inhibition (siRNA, PF-228 and PP2) in PAH-PASMCs induced a fivefold increase in apoptosis (percentage of terminal deoxynucleotidyl transferase dUTP nick end labelling), a 2.5-fold decrease in proliferation (%Ki67), an 18% decrease in cell migration (colorimetric assay) and a 50% decrease in cell invasion (wound healing).Suppressing PASMC migration by FAK inhibition inhibits PAH progression and may open a new therapeutic window in PAH.

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“…FAK is frequently overexpressed in various human cancers (14). Its overexpression highly correlates with tumor invasiveness; hence, FAK is widely pursued as a drug target for cancer therapy (15,16).…”

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confidence: 99%

Phosphatidylinositol 4,5-bisphosphate triggers activation of focal adhesion kinase by inducing clustering and conformational changes

Goñi

Epifano

Boskovic

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

124

186

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Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase (NRTK) with key roles in integrating growth and cell matrix adhesion signals, and FAK is a major driver of invasion and metastasis in cancer. Cell adhesion via integrin receptors is well known to trigger FAK signaling, and many of the players involved are known; however, mechanistically, FAK activation is not understood. Here, using a multidisciplinary approach, including biochemical, biophysical, structural, computational, and cell biology approaches, we provide a detailed view of a multistep activation mechanism of FAK initiated by phosphatidylinositol-4,5-bisphosphate [PI(4,5)P 2 ]. Interestingly, the mechanism differs from canonical NRTK activation and is tailored to the dual catalytic and scaffolding function of FAK. We find PI(4,5)P 2 induces clustering of FAK on the lipid bilayer by binding a basic region in the regulatory 4.1, ezrin, radixin, moesin homology (FERM) domain. In these clusters, PI(4,5)P 2 induces a partially open FAK conformation where the autophosphorylation site is exposed, facilitating efficient autophosphorylation and subsequent Src recruitment. However, PI(4,5)P 2 does not release autoinhibitory interactions; rather, Src phosphorylation of the activation loop in FAK results in release of the FERM/kinase tether and full catalytic activation. We propose that PI(4,5)P 2 and its generation in focal adhesions by the enzyme phosphatidylinositol 4-phosphate 5-kinase type Iγ are important in linking integrin signaling to FAK activation.cell signaling | phosphoinositides C ell attachment to the ECM is mediated via integrin transmembrane receptors on the cell surface. Integrin engagement to ECM components results in activation and clustering of integrins. In response to integrin activation, a large number of proteins are recruited to their cytoplasmic tails, resulting in the formation of focal adhesions (FAs) (1). On the one side, FAs are anchoring points for actomyosin stress fibers, which allow tension forces to build up when contracting fibers exert their pulling force via FAs against the ECM. On the other hand, integrin activation and the generation of tension trigger intricate signaling cascades. A central signaling component in FAs is the nonreceptor tyrosine kinase (NRTK) focal adhesion kinase (FAK).

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Therapeutic potential and limitations of new FAK inhibitors in the treatment of cancer

Cited by 93 publications

References 85 publications

Phosphoproteomic Profiling Identifies Focal Adhesion Kinase as a Mediator of Docetaxel Resistance in Castrate-Resistant Prostate Cancer

Phosphoproteomic Profiling Identifies Focal Adhesion Kinase as a Mediator of Docetaxel Resistance in Castrate-Resistant Prostate Cancer

Targeting cell motility in pulmonary arterial hypertension

Phosphatidylinositol 4,5-bisphosphate triggers activation of focal adhesion kinase by inducing clustering and conformational changes

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